Download or read book Mapping and Targeting Genetic and Physical Interactions at Scale written by Kyle Ford and published by . This book was released on 2022 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: Biological phenotypes are mediated by a network of functional interactions between genes, proteins, and other biomolecules present in the cell. While high-throughput screening efforts have largely mapped the role of individual genes in controlling phenotypes such as cellular proliferation, interactions between genes/proteins remain largely unmapped and untargeted. In this dissertation, we develop and apply novel screening methodologies to map and exploit interactions between genes/proteins. We use pairwise CRISPR-Cas9 mediated gene knockouts to map the full set of genetic interactions among cyclin-dependent kinases (CDKs) and interacting proteins, identifying several synthetic-lethal and synergistic relationships. We perform single-cell RNA sequencing on the CDK knockout populations, quantifying the cell-cycle effects and cell states mediated by individual CDK proteins. While CDKs are readily druggable via small molecules, many cancer drivers have structures which are not amenable to traditional pharmacological inhibition approaches. To address this challenge, we developed a peptide tiling (PepTile) approach to engineer protein inhibitors of cancer drivers and protein-protein interactions in general. By overexpressing pooled libraries of peptides within cancer cells, we map bioactive protein domains and identify peptides derived from key protein-protein interaction (PPI) interfaces which have strong anti-proliferative effects. We show that these peptides can be modified for extracellular delivery, functioning as anticancer drugs with micromolar IC50s. Finally, we demonstrated the versatility of the PepTile approach to alternative contexts, mining physical interactions to improve delivery of therapeutic payloads in vivo. We show our screening datasets can be used to train predictive models, with applications for future engineering efforts towards targeting and delivery of therapeutic biomolecules.
Download or read book Integrating Physical and Genetic Interaction Networks for Biological Pathway Discovery written by Sourav Bandyopadhyay and published by . This book was released on 2010 with total page 316 pages. Available in PDF, EPUB and Kindle. Book excerpt: The goal of understanding complex biological systems and how they are perturbed to cause disease has long been a central focus of biology. The past decade has seen the creation and maturation of a number of new technologies designed to study biological pathways on a genome-wide scale. Rather than obtaining information about the function of one gene or protein at a time, such approaches can offer insight into the activity of every gene and protein in the cell all in the context of one experiment. One fundamental mode of gathering biological insight is through identifying which proteins in the cell interact physically, such as those which form protein complexes or biochemical pathways. Techniques such as yeast-two hybrid and co-immunoprecipitation followed by mass spectrometry allow the determination of a physical interaction map which details binding interactions between proteins on a large scale. Another fundamental mode of biological discovery is through assaying genetic interactions which arise when mutations in two genes produce a phenotype that is surprising in light of each mutation's individual effects. For example a synthetic lethal genetic interaction is indicated when deletions in two genes which are not essential for viability cause lethality when deleted together. Genetic interaction maps can be determined in high-throughput via SGA (Synthetic Genetic Array) technology. In Chapter 2 we derive and analyze a large physical protein interaction map centered on a set of human protein kinases and show how biological insight can be derived from such large-scale screens. In Chapter 3, we develop methods for the comparison of such physical protein interaction maps between species in order to identify proteins whose function is conserved throughout millions of years of evolution. In Chapter 4 we develop algorithms to integrate both physical and genetic interactions together for the purpose of biological pathway discovery. Moreover, our approaches create maps of genetic interactions that provide a picture of the global organization of pathways and complexes within the cell, which we apply to create a map of functional relationships among protein complexes involved in chromosomal biology. In Chapter 6, we apply this approach in two different yeast species and discover that while physical protein interactions are largely conserved across species, many genetic interactions are rewired which gives us valuable insight into pathway architecture. Finally in Chapter 7, we focus on the discovery of genetic interactions involved in the DNA damage response by assaying how different gene mutants respond to a drug which causes DNA damage and then demonstration how this elucidates pathways involved in this process.
Download or read book Mapping Genetic Interactions written by Franco Joseph Vizeacoumar and published by . This book was released on 2021 with total page 361 pages. Available in PDF, EPUB and Kindle. Book excerpt: This volume details methods of identifying synthetic lethal, genetic interactions by various approaches in different model systems including human cancer cells. Chapters guide readers through genetic interactions in model organisms, RNA interference, CRISPR/Cas9 based genome editing technologies, drug-gene interactions, mapping chemical genetic interactions, synergistic drug-gene relations, single cell sequencing, gene expression profiling, and novel genetic interactions. Written in the format of the highly successful Methods in Molecular Biology series, each chapter includes an introduction to the topic, lists necessary materials and reagents, includes tips on troubleshooting and known pitfalls, and step-by-step, readily reproducible protocols. Authoritative and cutting-edge, Genetic Interaction Mapping aims to be a useful practical guide to researches to help further their study in this field.
Download or read book A Global Analysis of Synthetic Genetic Interactions a Genetic Analysis of Muscle Arm Development in Caenorhabditis Elegans written by Alexandra Byrne and published by . This book was released on 2009 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: Understanding gene function and genetic relationships is elemental in our efforts to better understand biological systems. Here, I describe a reliable high-throughput approach, Systematic Genetic Interaction analysis (SGI), capable of revealing both weak and strong genetic interactions in the nematode Caenorhabditis elegans. I also present evidence that UNC-73 functions cell-autonomously in an UNC-40 pathway to direct muscle arm extension in C. elegans. Previous efforts to systematically describe genetic interactions between redundant genes on a global scale either have focused on core biological processes in yeast or have surveyed catastrophic interactions in metazoans. I investigated synthetic genetic interactions between eleven 'query' mutants in conserved signal transduction pathways and hundreds of 'target' genes compromised by RNAi. A network of 1246 genetic interactions was uncovered through an unbiased global analysis of the interaction matrix, establishing the largest metazoan genetic interaction network to date. To investigate how genetic interactions connect genes on a systems-wide level, the SGI network was superimposed with existing networks of physical, genetic, phenotypic and co-expression interactions. Fifty-six putative functional modules were identified within the superimposed network, one of which regulates fat accumulation and is coordinated by bar-1(ga80)/beta-catenin interactions. This led to the discovery that SGI interactions link distinct functional modules on a global scale, which is a previously unappreciated level of organization within metazoan systems. In addition, I present evidence that the properties of genetic networks are conserved between C. elegans and S. cerevisiae, but that the connectivity of the interactions within the current networks is not. Although the buffering between functional modules may differ between species, studying these differences may provide insight into the evolution of divergent form and function. In C. elegans the postsynaptic membrane of the neuromuscular junction reaches its destination through an active process of guided cell extension. The worm has 95 body wall muscles (BWMs) that extend projections called 'muscle arms' to motor axons. The muscle arms harbour the postsynaptic elements of neuromuscular junctions. The stereotypical pattern of muscle arm extension was exploited in a forward genetic screen for new genes required for guided cell migration by looking for mutations that caused a reduction in the number of arms that extend to the motor axons. One of the resulting mutants was tr117, which extended half the number of arms compared to wild type animals. Genetic mapping, complementation tests, and sequencing revealed that tr117 was a mutation in unc-73/Trio, which encodes a guanine nucleotide exchange factor. Expression of UNC-73 specifically in the BWMs rescued the muscle arm development defects of unc-73(e936) mutants, indicating that UNC-73 functions cell-autonomously to regulate muscle arm extension. UNC-73::CFP was localized to muscle arm termini in a pattern similar to that of UNC-40/Dcc, which directs muscle arm extension. UNC-73 over-expression suppressed the Madd phenotype of unc-40 null worms and unc-73(e936) suppressed ectopic myopodia induced by UNC-40 over-expression. These results indicate that UNC-73 functions downstream of UNC-40 in a pathway that regulates muscle arm extension.
Download or read book Handbook of Systems Biology written by Marian Walhout and published by Academic Press. This book was released on 2012-12-31 with total page 553 pages. Available in PDF, EPUB and Kindle. Book excerpt: This book provides an entry point into Systems Biology for researchers in genetics, molecular biology, cell biology, microbiology and biomedical science to understand the key concepts to expanding their work. Chapters organized around broader themes of Organelles and Organisms, Systems Properties of Biological Processes, Cellular Networks, and Systems Biology and Disease discuss the development of concepts, the current applications, and the future prospects. Emphasis is placed on concepts and insights into the multi-disciplinary nature of the field as well as the importance of systems biology in human biological research. Technology, being an extremely important aspect of scientific progress overall, and in the creation of new fields in particular, is discussed in 'boxes' within each chapter to relate to appropriate topics. 2013 Honorable Mention for Single Volume Reference in Science from the Association of American Publishers' PROSE Awards Emphasizes the interdisciplinary nature of systems biology with contributions from leaders in a variety of disciplines Includes the latest research developments in human and animal models to assist with translational research Presents biological and computational aspects of the science side-by-side to facilitate collaboration between computational and biological researchers
Download or read book Mapping and Sequencing the Human Genome written by National Research Council and published by National Academies Press. This book was released on 1988-01-01 with total page 128 pages. Available in PDF, EPUB and Kindle. Book excerpt: There is growing enthusiasm in the scientific community about the prospect of mapping and sequencing the human genome, a monumental project that will have far-reaching consequences for medicine, biology, technology, and other fields. But how will such an effort be organized and funded? How will we develop the new technologies that are needed? What new legal, social, and ethical questions will be raised? Mapping and Sequencing the Human Genome is a blueprint for this proposed project. The authors offer a highly readable explanation of the technical aspects of genetic mapping and sequencing, and they recommend specific interim and long-range research goals, organizational strategies, and funding levels. They also outline some of the legal and social questions that might arise and urge their early consideration by policymakers.
Download or read book Next Generation Approaches for Understanding Physical and Genetic Networks written by Albi Celaj and published by . This book was released on 2018 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: Two approaches for understanding biological systems and gene function at a large scale are the mapping of protein-protein interactions (PPIs) and genetic interactions (GIs). PPIs map the physical connectivity structure of proteins, while GIs map dependence in phenotype when two or more genes are perturbed simultaneously. Current large-scale maps of PPIs and GIs are subject to various limitations, such as being measured in a single environment, and in the case of GI maps, a lack of exploration of complex dependencies beyond double knockouts. Here, I describe the analysis and development of emerging methods in PPIs and GIs to overcome these limitations. Analysis of a dynamic PPI assay (barcoded protein complementation assay; BC-PCA), finds that the majority of complexes (55%) change in abundance between conditions, and reveals a striking relationship between relative complex levels and relative mRNA expression during a diauxic shift from growth in glucose compared to ethanol (explaining an estimated 47% of the observed changes). A new method to analyze arbitrarily complex GIs in multiple environments is developed, and its ability to uncover new phenotypes for ABC transporters is demonstrated. Amongst the complex GIs, a four-knockout phenotype was found which confers unexpected resistance to the antifungal drug fluconazole. These methods and resulting analyzes demonstrate the need for an expansion of the scope of PPI and GI interaction mapping, and motivate their further development towards understanding living systems and gene function at a large scale.
Download or read book Large scale Mapping of Chemical genetic Interaction Phenotypes in Human Cells written by Christian Scheeder and published by . This book was released on 2022* with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Download or read book Biomolecular Networks written by Luonan Chen and published by John Wiley & Sons. This book was released on 2009-06-29 with total page 416 pages. Available in PDF, EPUB and Kindle. Book excerpt: Alternative techniques and tools for analyzing biomolecular networks With the recent rapid advances in molecular biology, high-throughput experimental methods have resulted in enormous amounts of data that can be used to study biomolecular networks in living organisms. With this development has come recognition of the fact that a complicated living organism cannot be fully understood by merely analyzing individual components. Rather, it is the interactions of components or biomolecular networks that are ultimately responsible for an organism's form and function. This book addresses the important need for a new set of computational tools to reveal essential biological mechanisms from a systems biology approach. Readers will get comprehensive coverage of analyzing biomolecular networks in cellular systems based on available experimental data with an emphasis on the aspects of network, system, integration, and engineering. Each topic is treated in depth with specific biological problems and novel computational methods: GENE NETWORKS—Transcriptional regulation; reconstruction of gene regulatory networks; and inference of transcriptional regulatory networks PROTEIN INTERACTION NETWORKS—Prediction of protein-protein interactions; topological structure of biomolecular networks; alignment of biomolecular networks; and network-based prediction of protein function METABOLIC NETWORKS AND SIGNALING NETWORKS—Analysis, reconstruction, and applications of metabolic networks; modeling and inference of signaling networks; and other topics and new trends In addition to theoretical results and methods, many computational software tools are referenced and available from the authors' Web sites. Biomolecular Networks is an indispensable reference for researchers and graduate students in bioinformatics, computational biology, systems biology, computer science, and applied mathematics.
Download or read book Network Medicine written by Joseph Loscalzo and published by Harvard University Press. This book was released on 2017-02-01 with total page 449 pages. Available in PDF, EPUB and Kindle. Book excerpt: Big data, genomics, and quantitative approaches to network-based analysis are combining to advance the frontiers of medicine as never before. With contributions from leading experts, Network Medicine introduces this rapidly evolving field of research, which promises to revolutionize the diagnosis and treatment of human diseases.
Download or read book Youmans and Winn Neurological Surgery E Book written by H. Richard Winn and published by Elsevier Health Sciences. This book was released on 2022-01-21 with total page 7439 pages. Available in PDF, EPUB and Kindle. Book excerpt: Widely regarded as the definitive reference in the field, Youmans and Winn Neurological Surgery offers unparalleled, multimedia coverage of the entirety of this complex specialty. Fully updated to reflect recent advances in the basic and clinical neurosciences, the 8th Edition covers everything you need to know about functional and restorative neurosurgery, deep brain stimulation, stem cell biology, radiological and nuclear imaging, and neuro-oncology, as well as minimally invasive surgeries in spine and peripheral nerve surgery, and endoscopic and other approaches for cranial procedures and cerebrovascular diseases. In four comprehensive volumes, Dr. H. Richard Winn and his expert team of editors and authors provide updated content, a significantly expanded video library, and hundreds of new video lectures that help you master new procedures, new technologies, and essential anatomic knowledge in neurosurgery. Discusses current topics such as diffusion tensor imaging, brain and spine robotic surgery, augmented reality as an aid in neurosurgery, AI and big data in neurosurgery, and neuroimaging in stereotactic functional neurosurgery. 55 new chapters provide cutting-edge information on Surgical Anatomy of the Spine, Precision Medicine in Neurosurgery, The Geriatric Patient, Neuroanesthesia During Pregnancy, Laser Interstitial Thermal Therapy for Epilepsy, Fetal Surgery for Myelomeningocele, Rehabilitation of Acute Spinal Cord Injury, Surgical Considerations for Patients with Polytrauma, Endovascular Approaches to Intracranial Aneurysms, and much more. Hundreds of all-new video lectures clarify key concepts in techniques, cases, and surgical management and evaluation. Notable lecture videos include multiple videos on Thalamotomy for Focal Hand Dystonia and a video to accompany a new chapter on the Basic Science of Brain Metastases. An extensive video library contains stunning anatomy videos and videos demonstrating intraoperative procedures with more than 800 videos in all. Each clinical section contains chapters on technology specific to a clinical area. Each section contains a chapter providing an overview from experienced Section Editors, including a report on ongoing controversies within that subspecialty. Enhanced eBook version included with purchase. Your enhanced eBook allows you to access all of the text, figures, and references from the book on a variety of devices.
Download or read book An Omics Perspective on Cancer Research written by William C.S. Cho and published by Springer Science & Business Media. This book was released on 2010-04-07 with total page 269 pages. Available in PDF, EPUB and Kindle. Book excerpt: Omics is an emerging and exciting area in the field of science and medicine. Numerous promising developments have been elucidated using omics (including genomics, transcriptomics, epigenomics, proteomics, metabolomics, interactomics, cytomics and bioinformatics) in cancer research. The development of high-throughput technologies that permit the solution of deciphering cancer from higher dimensionality will provide a knowledge base which changes the face of cancer understanding and therapeutics. This is the first book to provide such a comprehensive coverage of a rapidly evolving area written by leading experts in the field of omics. It complies and details cutting-edge cancer research that covers the broad advances in the field and its application from cancer-associated gene discovery to drug target validation. It also highlights the potential of using integration approach for cancer research. This unique and timely book provides a thorough overview of developing omics, which will appeal to anyone involved in cancer research. It will be a useful reference book for graduate students of different subjects (medicine, biology, engineering, etc) and senior scientists interested in the fascinating area of advanced technologies in cancer research. Readership: This is a precious book for all types of readers – cancer researchers, oncologists, pathologists, biologists, clinical chemists, pharmacologists, pharmaceutical specialists, biostatisticians, and bioinformaticists who want to expand their knowledge in cancer research.
Download or read book Sourcebook of Models for Biomedical Research written by P. Michael Conn and published by Springer Science & Business Media. This book was released on 2008-03-07 with total page 756 pages. Available in PDF, EPUB and Kindle. Book excerpt: The collection of systems represented in this volume is a unique effort to reflect the diversity and utility of models used in biomedicine. That utility is based on the consideration that observations made in particular organisms will provide insight into the workings of other, more complex systems. This volume is therefore a comprehensive and extensive collection of these important medical parallels.
Download or read book Modern Genetic Analysis written by Anthony J.F. Griffiths and published by Macmillan. This book was released on 2002-02-22 with total page 776 pages. Available in PDF, EPUB and Kindle. Book excerpt: Modern Genetic Analysis, Second Edition, the second introductory genetics textbook W.H. Freeman has published by the Griffiths author team, implements an innovative approach to teaching genetics. Rather than presenting material in historical order, Modern Genetic Analysis, Second Edition integrates molecular genetics with classical genetics. The integrated approach provides students with a concrete foundation in molecules, while simultaneously building an understanding of the more abstract elements of transmission genetics. Modern Genetic Analysis, Second Editionalso incorporates new pedagogy, improved chapter organization, enhanced art, and an appealing overall design.
Download or read book Microbial Functional Genomics written by Jizhong Zhou and published by John Wiley & Sons. This book was released on 2004-03-19 with total page 624 pages. Available in PDF, EPUB and Kindle. Book excerpt: Microbial Functional Genomics offers a timely summary of the principles, approaches, and applications. It presents a comprehensive review of microbial functional genomics, covering microbial diversity, microbial genome sequencing, genomic technologies, genome-wide functional analysis, applied functional genomics, and future directions. An introduction will offer a definition of the field and an overview of the historical and comparative genomics aspects.
Download or read book Physical Biology of the Cell written by Rob Phillips and published by Garland Science. This book was released on 2012-10-29 with total page 1088 pages. Available in PDF, EPUB and Kindle. Book excerpt: Physical Biology of the Cell is a textbook for a first course in physical biology or biophysics for undergraduate or graduate students. It maps the huge and complex landscape of cell and molecular biology from the distinct perspective of physical biology. As a key organizing principle, the proximity of topics is based on the physical concepts that
Download or read book Genome Research written by and published by . This book was released on 2008 with total page 1494 pages. Available in PDF, EPUB and Kindle. Book excerpt:
